Department of Gerontology and Geriatrics, The First Affiliated Hospital of China Medical University, Shenyang, China.
Department of Gerontology and Geriatrics, The First Affiliated Hospital of China Medical University, Shenyang, China.
Brain Res Bull. 2020 Jul;160:98-106. doi: 10.1016/j.brainresbull.2020.04.022. Epub 2020 May 5.
Hypoglycemia-induced brain injury is a potential complication of insulin therapy in diabetic patients. Severe hypoglycemia triggers a cascade of events in vulnerable neurons that may lead to neuronal death and cognitive impairment even after glucose normalization. Oxidative stress and the activation of poly (ADP-ribose) polymerase-1 (PARP-1) are key events in this cascade. The production of reactive oxygen species (ROS) induces DNA damage and the consequent PARP-1 activation, which depletes NAD and ATP, resulting in brain injury. One of the key precursors of NAD is nicotinamide mononucleotide (NMN), which is converted to NAD and reduces production of ROS. Here we investigated whether NMN could reduce brain injury after severe hypoglycemia. We used a rat model of insulin-induced severe hypoglycemia and injected NMN (500 mmg/kg, i.p., one week) following 30 min of severe hypoglycemia, at the time of glucose administration. One week after severe hypoglycemia, hippocampal long-term potentiation (LTP), an electrophysiogic assay of synaptic plasticity, was examined and neuronal damage was assessed by Hematoxylin-Eosin staining. ROS accumulation, PARP-1 activation, NAD and ATP levels in hippocampus were also measured. Cognitive function was assessed using the Morris water maze 6 weeks after severe hypoglycemia. The addition of NMN reduced neuron death by 83 ± 3% (P < 0.05) after severe hypoglycemia. The hippocampal LTP was significantly reduced by severe hypoglycemia but showed recovery in the NMN addition group. NMN treatment also attenuated the severe hypoglycemia-induced spatial learning and memory impairment. Mechanically, we showed that NMN administration decreased ROS accumulation, suppressed PARP-1 activation, and restored levels of NAD and ATP in hippocampus. All these protective effects were reversed by 3-acetylpyridine (3-AP), which generates inactive NAD. In summary, NMN administration following severe hypoglycemia could ameliorate neuronal damage and cognitive impairment caused by severe hypoglycemia. These results suggest that NMN may be a promising therapeutic drug to prevent hypoglycemia-induced brain injury.
低血糖诱导的脑损伤是糖尿病患者胰岛素治疗的潜在并发症。严重低血糖会触发脆弱神经元中的级联反应，即使葡萄糖恢复正常，也可能导致神经元死亡和认知障碍。氧化应激和聚（ADP-核糖）聚合酶-1（PARP-1）的激活是该级联反应中的关键事件。活性氧（ROS）的产生会导致 DNA 损伤和随后的 PARP-1 激活，从而耗尽 NAD 和 ATP，导致脑损伤。NAD 的关键前体之一是烟酰胺单核苷酸（NMN），它可转化为 NAD 并减少 ROS 的产生。在这里，我们研究了 NMN 是否可以减轻严重低血糖后的脑损伤。我们使用胰岛素诱导的严重低血糖大鼠模型，在严重低血糖 30 分钟后（即给予葡萄糖时），腹腔注射 NMN（500mmg/kg，一周一次）。严重低血糖后一周，通过海马长时程增强（LTP）检测评估海马突触可塑性的电生理测定，通过苏木精-伊红染色评估神经元损伤。还测量了海马中 ROS 积累、PARP-1 激活、NAD 和 ATP 水平。严重低血糖 6 周后，通过 Morris 水迷宫评估认知功能。添加 NMN 可使严重低血糖后神经元死亡减少 83±3%（P<0.05）。严重低血糖显著降低海马 LTP，但在添加 NMN 的组中恢复。NMN 治疗还减轻了严重低血糖引起的空间学习和记忆障碍。从机制上讲，我们发现 NMN 给药可减少 ROS 积累，抑制 PARP-1 激活，并恢复海马中 NAD 和 ATP 的水平。3-乙酰吡啶（3-AP）可逆转所有这些保护作用，3-AP 可产生无活性的 NAD。总之，严重低血糖后给予 NMN 可改善严重低血糖引起的神经元损伤和认知障碍。这些结果表明，NMN 可能是预防低血糖引起的脑损伤的有前途的治疗药物。
